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==Crystal Structure of KRAS G12D with compound 24 (4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2S,4S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol) bound== | ==Crystal Structure of KRAS G12D with compound 24 (4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2S,4S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol) bound== | ||
<StructureSection load='7rt3' size='340' side='right'caption='[[7rt3]]' scene=''> | <StructureSection load='7rt3' size='340' side='right'caption='[[7rt3]], [[Resolution|resolution]] 1.56Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RT3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RT3 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7rt3]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RT3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RT3 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7rt3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rt3 OCA], [https://pdbe.org/7rt3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rt3 RCSB], [https://www.ebi.ac.uk/pdbsum/7rt3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rt3 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7NZ:4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2S,4S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol'>7NZ</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7rpz|7rpz]]</div></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Small_monomeric_GTPase Small monomeric GTPase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.5.2 3.6.5.2] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7rt3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rt3 OCA], [https://pdbe.org/7rt3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rt3 RCSB], [https://www.ebi.ac.uk/pdbsum/7rt3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rt3 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
KRAS(G12D), the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRAS(G12C), selective inhibition of KRAS(G12D) presents a significant challenge due to the requirement of inhibitors to bind KRAS(G12D) with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRAS(G12D) inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRAS(G12D) mutant xenograft mouse tumor model. | |||
Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS(G12D) Inhibitor.,Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, Dahlke JR, Fell JB, Fischer JP, Gunn RJ, Hallin J, Laguer J, Lawson JD, Medwid J, Newhouse B, Nguyen P, O'Leary JM, Olson P, Pajk S, Rahbaek L, Rodriguez M, Smith CR, Tang TP, Thomas NC, Vanderpool D, Vigers GP, Christensen JG, Marx MA J Med Chem. 2021 Dec 10. doi: 10.1021/acs.jmedchem.1c01688. PMID:34889605<ref>PMID:34889605</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7rt3" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Gunn | [[Category: Small monomeric GTPase]] | ||
[[Category: Lawson | [[Category: Gunn, R G]] | ||
[[Category: Marx | [[Category: Lawson, J D]] | ||
[[Category: Thomas | [[Category: Marx, M A]] | ||
[[Category: Xiaolun W]] | [[Category: Thomas, N C]] | ||
[[Category: Xiaolun, W]] | |||
[[Category: G12d]] | |||
[[Category: Gtpase]] | |||
[[Category: Hydrolase-inhibitor complex]] | |||
[[Category: Kra]] | |||
[[Category: Kras4b]] | |||
[[Category: Mrtx-1133]] | |||
[[Category: Oncology]] | |||
[[Category: Oncoprotein]] | |||
Revision as of 10:26, 9 March 2022
Crystal Structure of KRAS G12D with compound 24 (4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2S,4S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol) bound
Structural highlights
Publication Abstract from PubMedKRAS(G12D), the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRAS(G12C), selective inhibition of KRAS(G12D) presents a significant challenge due to the requirement of inhibitors to bind KRAS(G12D) with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRAS(G12D) inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRAS(G12D) mutant xenograft mouse tumor model. Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS(G12D) Inhibitor.,Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, Dahlke JR, Fell JB, Fischer JP, Gunn RJ, Hallin J, Laguer J, Lawson JD, Medwid J, Newhouse B, Nguyen P, O'Leary JM, Olson P, Pajk S, Rahbaek L, Rodriguez M, Smith CR, Tang TP, Thomas NC, Vanderpool D, Vigers GP, Christensen JG, Marx MA J Med Chem. 2021 Dec 10. doi: 10.1021/acs.jmedchem.1c01688. PMID:34889605[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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